|Year : 2015 | Volume
| Issue : 5 | Page : 182-189
Correlation between liver function tests and metabolic syndrome in hepatitis-free elderly
Hung-Sheng Shang1, Bing-Heng Yang1, Cherng-Lih Perng2, Sheng-Hue Tang1, Chien-Ming Lin3, Jin-Biou Chang1
1 Division of Clinical Pathology, Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
2 Division of Clinical Pathology, Department of Pathology; Graduate Institute of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
3 Department of Pediatrics, Tri-Service General Hospital; Graduate Institute of Medical Science, National Defense Medical Center, Taipei, Taiwan
|Date of Submission||17-Jun-2015|
|Date of Decision||16-Jul-2015|
|Date of Acceptance||12-Aug-2015|
|Date of Web Publication||22-Oct-2015|
Division of Clinical Pathology, Tri-Service General Hospital, No. 325, Sec. 2, Chenggong Road, Neihu District, Taipei City 114
Source of Support: None, Conflict of Interest: None
Background: We aimed to investigate the relationship between liver function tests (LFTs) and metabolic syndrome (MetS) as several studies have shown positive correlations between some of the LFTs, including alanine aminotransferase (ALT) and γ-glutamyl transpeptidase (γ-GT), and MetS but have not fully explored the same in the elderly. Owing to the progress in public health, the aging of the general population becomes a major issue. Design: We enrolled subjects aged over 60 years who underwent routine health checkups in a Health Screening Center after excluding subjects with a history of hepatitis B or C infection, excessive alcohol consumption, liver fibrosis, cirrhosis, acute hepatitis, diabetes, hypertension, dyslipidemia, cardiovascular disease, or receiving medications for these diseases. Finally, 9,282 participants were eligible for analysis. Statistical Analysis: All data were tested for normal distribution with the Kolmogorov-Smirnov test and for homogeneity of variances with the Levene's test. A t-test was used to evaluate the differences between the two groups. Univariate and multivariate regressions were used to observe correlations between different parameters. Receiver operating characteristic curves of each LFT were used to predict MetS. Areas under curves and 95% confidence interval were also estimated and compared. Results: With the exception of aspartate aminotransferase and α-fetal protein, the results of LFTs, including total and direct bilirubin, alkaline phosphatase (ALP), ALT, and γ-GT, were altered in the group with MetS. Furthermore, the levels of γ-GT in men and ALP in women were independently associated with all MetS components and had the highest areas under receiver operating characteristic curves. Conclusion: Abnormal LFTs are highly correlated with MetS in the hepatitis-free elderly, with levels of γ-GT in men and ALP in women being the most important factors. LFTs may represent an auxiliary tool for the detection of MetS.
Keywords: Liver function tests, metabolic syndrome, elderly
|How to cite this article:|
Shang HS, Yang BH, Perng CL, Tang SH, Lin CM, Chang JB. Correlation between liver function tests and metabolic syndrome in hepatitis-free elderly. J Med Sci 2015;35:182-9
|How to cite this URL:|
Shang HS, Yang BH, Perng CL, Tang SH, Lin CM, Chang JB. Correlation between liver function tests and metabolic syndrome in hepatitis-free elderly. J Med Sci [serial online] 2015 [cited 2019 Oct 19];35:182-9. Available from: http://www.jmedscindmc.com/text.asp?2015/35/5/182/167708
| Introduction|| |
The combination of impaired glucose tolerance, central obesity, hypertension, and dyslipidemia is termed metabolic syndrome (MetS). , However, elevated levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) are also associated with MetS. ,,,,,,,,
Many abnormal liver function test (LFT) cases are due to nonalcoholic fatty liver disease (NAFLD).  To avoid bias, we enrolled 9,282 subjects over 60 years old without liver disease. Thus, the relationship between levels of AST, ALT, ALP, γ-glutamyl transpeptidase (γ-GT), total bilirubin (T-Bil), direct bilirubin (D-Bil), and α-fetoprotein (AFP), and MetS components was evaluated to enable early MetS detection.
| Methods|| |
We enrolled subjects aged over 60 years who underwent routine health checkups between 1999 and 2007 at an MJ Health Screening Center. MJ Health Screening Centers are private clinics located throughout Taiwan that provide regular health examinations to their members. Originally, 27,679 subjects were randomly selected. The following exclusion steps were performed to recruit individuals who fit our study purposes:
- 1,121 subjects were excluded because of missing data on MetS components, LFTs, hepatitis B core antibody, hepatitis B surface antigen, or hepatitis C virus antibody tests.
- 7,639 subjects with a history of diabetes, hypertension, dyslipidemia, cardiovascular disease, or receiving medications for these diseases or other medications known to affect components of MetS were excluded including estrogen.
- 4,785 subjects were excluded because of chronic hepatitis B or C infection.
- 4,852 subjects with a history of excessive alcohol consumption (>20 g/day for men and >10 g/day for women), liver fibrosis, cirrhosis, hepatobiliary operation, or acute hepatitis were also excluded from this study.
The remaining 9,282 subjects were eligible for analysis. All subjects were delinked. To avoid data of the same subject but from different years were analyzed repeatedly; data with the same sequential number were only selected once. The study protocol was approved by the institutional review board of MJ Health Screening Centers, and informed consent was obtained from all the participants.
Participants visited the clinic at 8 AM after at least a 10-h fast. Information about medical history, lifestyle, alcohol intake, smoking, and physical exercise was obtained through an interview with senior nursing staff. A complete physical examination was conducted, and waist circumference was taken at the midway point between the inferior margin of the last rib and the crest of the ilium, in a horizontal plane. After resting for 5 min in a sitting position, systolic and diastolic blood pressures were measured on the right arm using a computerized automatic mercury sphygmomanometer. A venous blood sample was collected for biochemical study. For the analysis of fasting plasma glucose (FPG) and lipid proﬁles, plasma was separated from blood within 1 h and stored at −30°C. FPG was assessed using the glucose oxidase method (YSI 203 glucose analyzer, Scientiﬁc Division, Yellow Springs Instruments, Yellow Springs, OH, USA). Total cholesterol and triglycerides were measured with a Fuji Dri-Chem 3000 analyzer (Fuji Photo Film, Minato-Ku, Tokyo, Japan) using the dry multilayer analytical slide method. Serum high-density lipoprotein cholesterol concentration was analyzed using an enzymatic cholesterol assay following dextran sulfate precipitation. AST and ALT levels were measured by the ultraviolet method with P5P (ARCHITECT c System, Abbott Diagnostics, Lake Forest, IL, USA). Hepatitis C antibody, hepatitis B surface antigen, and hepatitis B core antibody were detected by using chemiluminescent microparticle immunoassays (ARCHITECT i System, Abbott Diagnostics). LFTs including γ-GT, D-Bil, T-Bil, ALT, AST, AFP, and ALP were performed using a CX7 biochemistry analyzer (Beckman, Fullerton, CA, USA).
Deﬁnition of metabolic syndrome
The harmonized criteria of 2009  were used for the detection of MetS. Waist circumference was adjusted to ≥90 and ≥80 cm for Taiwanese men and women, respectively.  The other 4 criteria remained the same: Systolic blood pressure ≥130 mmHg or diastolic blood pressure ≥85 mmHg, triglycerides ≥150 mg/dL, FPG ≥100 mg/dL, high-density lipoprotein cholesterol ≤40 and ≤50 mg/dL for men and women, respectively, or intake of related medications. Subjects had to satisfy at least 3 criteria to be diagnosed with MetS. Based on these criteria, patients were assigned to the group with or without MetS.
An abdominal sonogram was recorded for every participant using a high-resolution B-mode scanner (SSA-240A, Toshiba Corporation, Tokyo, Japan), and the results were interpreted by 2 highly experienced radiologists. The radiologists participated in regular conferences to discuss all the radiologic results with the aim to reduce expert bias. Normal liver echogenicity was assigned a score of 0, whereas increased echogenicity was assigned a score of 1 based on liver-kidney echo discrepancy and loss of echoes from the walls of the portal veins.  Liver cyst, mass, and cirrhosis were all excluded by the radiologist.
The data were analyzed with SPSS version 18.0 (SPSS, Chicago, IL, USA). All data were tested for normal distribution with the Kolmogorov-Smirnov test and for homogeneity of variances with the Levene's test. Continuous variables were expressed as mean ± standard error of the mean. The t-test was used to evaluate the differences between the two groups. Univariate and multivariate regressions were used to observe correlations between different parameters. Receiver operating characteristic curves of each LFT were used to predict MetS. Areas under curves (AUCs) and 95% confidence interval were also estimated and compared. All statistical tests were two-sided and considered statistically significant when P < 0.05.
| Results|| |
[Table 1] summarizes the demographic data of the 9,282 subjects with and without MetS. Among all the LFTs, only the differences in the levels of AST and AFP between the groups with and without MetS did not reach statistical significance for both sexes. In addition, D-Bil in men also showed a borderline P-value of 0.051. The results of Pearson's correlation analysis between all the biochemical parameters of the liver and the MetS components are shown in [Table 2]. It can be noted that, although the relationships are not exactly the same in men and women, T-Bil and D-Bil, as well as ALP were related mainly to triglycerides and high-density lipoprotein cholesterol. In men, γ-GT and ALT were strongly correlated with MetS, but in women such relationships could only be found for waist circumference, FPG, and triglycerides. In contrast to γ-GT and ALT, AFP had no positive correlations, except with FPG in women. The relationships revealed with multiple regression analysis were generally similar to those found with the Pearson's correlation analysis [Table 3].
|Table 1: Demographic data of study subjects with and without metabolic syndrome|
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|Table 2: Pearson's correlation coefficients between metabolic syndrome components and each liver function test|
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|Table 3: Multivariate regression analysis of correlations between metabolic syndrome components and liver function tests used as independent variables|
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In receiver operating characteristic curve analysis, only AST in both sexes and AFP in women failed to show significant associations with MetS. The highest values of AUC were found for γ-GT (0.597 ± 0.014) in men and ALP (0.601 ± 0.011) in women. Although these values were not high enough to have predictive power, it should be pointed out that the study participants were healthier than a typical study population. Therefore, the extreme end of the data distribution was lost, which affected the capability to predict MetS from AUC. The second highest AUC values were found for D-Bil in men and T-Bil in women. However, these values were significantly lower than the highest AUCs in both genders.
| Discussion|| |
Although several studies reported on the relationships between LFTs and MetS, it has not been clarified which LFTs exhibit the strongest associations, especially in the elderly. In the current study, we found that γ-GT in men and ALP in women have the highest correlations with MetS. Moreover, the extents of these correlations are different in men and women. Our results indicate intriguing roles of abnormal LFTs, which warrants further investigation.
The positive relationship between γ-GT and MetS in hepatitis-free subjects has been verified in numerous studies. ,,,,,, For example, a meta-analysis was conducted of 9 prospective cohort studies including 47,499 participants and 5,009 cases of MetS. These studies examined the risks of developing MetS in subjects with the highest and lowest γ-GT levels. The pooled relative risk was 1.63 for the group with high γ-GT.  Another 4-year cohort study had similar findings. It was noted that, in 3,698 Korean male workers, γ-GT had a positive correlation with the risk of MetS incidence.  Furthermore, Kang et al. found that, as the quartile of serum γ-GT level increased in 3,246 adults (age: 20-70 years old; 1,622 men and 1,624 women) who visited Center for Health Promotion in Pusan National University Hospital for a medical checkup, the number of components of MetS and the prevalence of MetS also increased.  In addition to its relationship with MetS, γ-GT has also been shown to be associated with dyslipidemia and abnormal glucose tolerance. This suggests that serum γ-GT probably interacts with MetS through its effects on hepatic insulin resistance, which is not related to NAFLD.  γ-GT level, even when in the normal range, was also found to be significantly associated with anti-oxidative stress activity, accumulation of oxidative stress, MetS, and atherosclerosis. Measuring the γ-GT level is easy and inexpensive, and it can be used as a sensitive marker of oxidative stress and MetS.  Overall, our results are consistent with those of the main studies in this field. However, we observed a stronger correlation between the γ-GT level and MetS in the elderly men. The reason for this sex-related difference is currently unknown.
Some studies have suggested that there is a link between increased ALP and a greater likelihood of having MetS and its components. ,,,,, For example, Kim et al. examined the relationship between the serum ALP level and the development of MetS in 14,224 middle-aged Korean men during a 4-year period. The results showed that higher serum ALP level correlated positively with body fat mass and visceral fat mass. At the baseline, none of the participants had MetS. However, after 4 years, 1,179 developed MetS and, at the same time, serum ALP levels also increased.  Another cross-sectional study conducted in Croatia revealed similar finding in a group of independently living elderly persons aged 70-90 years. Men with MetS had higher levels of ALP.  Our results are in line with these studies. Furthermore, we also showed that ALP was most tightly associated with MetS in elderly women.
In agreement with published studies, our results suggest a negative correlation between bilirubin levels and the prevalence of MetS and its components. ,,,,, For instance, a cross-sectional study including 12,342 Korean adults showed that high bilirubin was associated with significantly lower odds ratio of developing MetS.  Another large-scale cross-sectional study, also performed in Korea, demonstrated that T-Bil level was inversely associated with the prevalence of MetS, even after the adjustment for other risk factors of MetS. 
The main strength of this study is that it is the first to explore the correlations between the results of different LFTs and MetS in the elderly. In addition, we also provide new information regarding sex-related differences in these correlations. However, the study has several limitations. First, the subjects were recruited from a single private health screening center. Thus, they had better than average economic status and likely received more medical support. However, we believe that the relationships that we observed are not affected by these confounding factors. Second, it is generally accepted that the core defect in MetS is insulin resistance, which was not evaluated in our study. Third, since subjects receiving medications for the treatment of MetS components were excluded from this study, we could not analyze the subpopulation with more severe MetS. Although this precluded the complete evaluation of the relationship between LFTs and MetS, it would be difficult and unethical to recruit subjects with severe MetS who did not receive any treatment. Furthermore, the strict exclusion criteria that we employed facilitated a precise assessment of the association between LFTs and MetS. Finally, although there are some important markers that are highly related to MetS, we still cannot analyze them in the present study. This is mainly due to the fact that our data were derived from the health examination. If any markers that were not measured or collected in the beginning, it would not be possible to do further evaluation.
| Conclusion|| |
Abnormal LFTs are associated with MetS in the elderly in a sex-dependent manner. In particular, γ-GT in men and ALP in women showed the highest associations with MetS. Abnormal LFT values could serve as a sensitive indicator for the early detection of MetS in the elderly.
| Acknowledgments|| |
The authors thank the personnel of the MJ Health Screening Center for providing the data.
| References|| |
Shin JA, Lee JH, Lim SY, Ha HS, Kwon HS, Park YM, et al.
Metabolic syndrome as a predictor of type 2 diabetes, and its clinical interpretations and usefulness. J Diabetes Investig 2013;4:334-43.
Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: Diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med 1998;15:539-53.
Stone NJ, Bilek S, Rosenbaum S. Recent National Cholesterol Education Program Adult Treatment Panel III update: Adjustments and options. Am J Cardiol 2005;96:53E-9E.
Zheng JQ, Wang K, Pei D, Chen YL, Chang YL, Hsu CH, et al.
Improvement of abnormal liver enzymes after rosiglitazone treatment in Chinese type 2 diabetes. Indian J Pharmacol 2012;44:372-6.
Hsu CH, Wang JY, Chen YL, Liu CC, Chang YL, Chen HS, et al.
Relationships between alanine aminotransferase levels, abnormal liver echogenicity, and metabolic syndrome. J Am Board Fam Med 2011;24:407-14.
Hanley AJ, Williams K, Festa A, Wagenknecht LE, D′Agostino RB Jr, Haffner SM. Liver markers and development of the metabolic syndrome: The insulin resistance atherosclerosis study. Diabetes 2005;54:3140-7.
Schindhelm RK, Dekker JM, Nijpels G, Stehouwer CD, Bouter LM, Heine RJ, et al.
Alanine aminotransferase and the 6-year risk of the metabolic syndrome in Caucasian men and women: The Hoorn study. Diabet Med 2007;24:430-5.
Olynyk JK, Knuiman MW, Divitini ML, Davis TM, Beilby J, Hung J. Serum alanine aminotransferase, metabolic syndrome, and cardiovascular disease in an Australian population. Am J Gastroenterol 2009;104:1715-22.
Xia MF, Yan HM, Lin HD, Bian H, Pan BS, Yao XZ, et al.
Elevation of liver enzymes within the normal limits and metabolic syndrome. Clin Exp Pharmacol Physiol 2011;38:373-9.
Yokoyama H. Gamma glutamyl transpeptidase (gammaGTP) in the era of metabolic syndrome. Nihon Arukoru Yakubutsu Igakkai Zasshi 2007;42:110-24.
Vítek L. The role of bilirubin in diabetes, metabolic syndrome, and cardiovascular diseases. Front Pharmacol 2012;3:55.
Wu Y, Li M, Xu M, Bi Y, Li X, Chen Y, et al.
Low serum total bilirubin concentrations are associated with increased prevalence of metabolic syndrome in Chinese. J Diabetes 2011;3:217-24.
Athyros VG, Giouleme O, Ganotakis ES, Elisaf M, Tziomalos K, Vassiliadis T, et al.
Safety and impact on cardiovascular events of long-term multifactorial treatment in patients with metabolic syndrome and abnormal liver function tests: A post hoc
analysis of the randomised ATTEMPT study. Arch Med Sci 2011;7:796-805.
Alberti KG, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI, Donato KA, et al.
Harmonizing the metabolic syndrome: A joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 2009;120:1640-5.
Saverymuttu SH, Joseph AE, Maxwell JD. Ultrasound scanning in the detection of hepatic fibrosis and steatosis. Br Med J (Clin Res Ed) 1986;292:13-5.
Liu CF, Zhou WN, Fang NY. Gamma-glutamyltransferase levels and risk of metabolic syndrome: A meta-analysis of prospective cohort studies. Int J Clin Pract 2012;66:692-8.
Demir B, Temizhan A, Keskin G, Baser K, Turak O, Cay S. Comparison of serum gamma-glutamyltransferase levels between patients with cardiac syndrome X and healthy asymptomatic individuals. Kardiol Pol 2012;70:31-7.
Bian AL, Wang XF. Relationship between serum gamma-glutamyltransferase and the risk of metabolic syndrome. Zhonghua Liu Xing Bing Xue Za Zhi 2011;32:625-8.
Kawamoto R, Tabara Y, Kohara K, Miki T, Kusunoki T, Takayama S, et al.
High-sensitivity C-reactive protein and gamma-glutamyl transferase levels are synergistically associated with metabolic syndrome in community-dwelling persons. Cardiovasc Diabetol 2010;9:87.
Kang YH, Min HK, Son SM, Kim IJ, Kim YK. The association of serum gamma glutamyltransferase with components of the metabolic syndrome in the Korean adults. Diabetes Res Clin Pract 2007;77: 306-13.
Pandeya SN, Kumar A, Singh BN, Mishra DN. Synthesis and biological activity of isodithiobiurets, dithiobiurets, and dithiazoles. Pharm Res 1987;4:321-6.
Tariq M, Parmar NS, Ageel AM. Gastric and duodenal antiulcer and cytoprotective effects of proglumide in rats. J Pharmacol Exp Ther 1987;241:602-7.
Nakagawa H, Isogawa A, Tateishi R, Tani M, Yoshida H, Yamakado M, et al.
Serum gamma-glutamyltransferase level is associated with serum superoxide dismutase activity and metabolic syndrome in a Japanese population. J Gastroenterol 2012;47:187-94.
Cheung CL, Tan KC, Lam KS, Cheung BM. The relationship between glucose metabolism, metabolic syndrome, and bone-specific alkaline phosphatase: A structural equation modeling approach. J Clin Endocrinol Metab 2013;98:3856-63.
Kim MK, Baek KH, Kang MI, Park SE, Rhee EJ, Park CY, et al.
Serum alkaline phosphatase, body composition, and risk of metabolic syndrome in middle-aged Korean. Endocr J 2013;60:321-8.
Pašalic D, Dodig S, Corovic N, Pizent A, Jurasovic J, Pavlovic M. High prevalence of metabolic syndrome in an elderly Croatian population - A multicentre study. Public Health Nutr 2011;14:1650-7.
Kelishadi R, Cook SR, Adibi A, Faghihimani Z, Ghatrehsamani S, Beihaghi A, et al.
Association of the components of the metabolic syndrome with non-alcoholic fatty liver disease among normal-weight, overweight and obese children and adolescents. Diabetol Metab Syndr 2009;1:29.
Liu M, Yan HM, Gao X, Gao J. Association of abnormality of liver enzymes and metabolic syndrome in patients with nonalcoholic fatty liver disease. Zhonghua Yi Xue Za Zhi 2007;87:253-5.
Guize L, Thomas F, Pannier B, Bean K, Danchin N, Bénétos A. Metabolic syndrome: Prevalence, risk factors and mortality in a French population of 62 000 subjects. Bull Acad Natl Med 2006;190:685-97.
Guzek M, Jakubowski Z, Bandosz P, Wyrzykowski B, Smoczynski M, Jabloiska A, et al.
Inverse association of serum bilirubin with metabolic syndrome and insulin resistance in Polish population. Przegl Epidemiol 2012;66:495-501.
Oda E, Aizawa Y. Total bilirubin is inversely associated with metabolic syndrome but not a risk factor for metabolic syndrome in Japanese men and women. Acta Diabetol 2013;50:417-22.
Choi SH, Yun KE, Choi HJ. Relationships between serum total bilirubin levels and metabolic syndrome in Korean adults. Nutr Metab Cardiovasc Dis 2013;23: 31-7.
Kwon KM, Kam JH, Kim MY, Kim MY, Chung CH, Kim JK, et al.
Inverse association between total bilirubin and metabolic syndrome in rural Korean women. J Womens Health (Larchmt) 2011;20:963-9.
[Table 1], [Table 2], [Table 3]